N-(alpha-methyl-2, 4-dichlorophenethyl) hydroxylamine and its salts



United States Patent Ofiflce 3,ll8,933 Patented Jan. 21, 1964 3,118,933N-(a-METHYL-Z,4-DICHLORQPHENETHYL) HYDROXYLAMlNE AND ITS SALTS MosesWolf Goldberg, Upper Montclair, and Marcel Muller, Passaic, Nl,assignors to Hoifmann-La Roche The, Nntley, Ni, a corporation of New.l'ersey No Drawing. Filed Dec. 28, 1959, 'Ser. No. 862,050 5 Claims.(Cl. 260-501) This invention relates to novel chemical compounds and toa novel method for preparing the same. More particularly, the inventionrelates to the novel compounds: N-(Otmethyl-2,4-dichlorophenethyl)hydroxylamine and acid addition saltsthereof; and to methods of preparing said novel compounds.

N- a-methyl-2,4-dichlorophenethyl hydroxylamine and acid addition saltsthereof, more particularly acid addition salts thereof withpharmaceutically acceptable acids, are useful as appetite reducinagents. By pharmaceutically acceptable acids is meant those inorganicand organic acids which are encountered in pharmaceutical practice, suchas hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid,phosphoric acid, acetic acid, malic acid, oxalic acid, p-toluenesulfonicacid, and the like.

N zx-methyl-Z,4-dichlorophenethyl) hydroxyl amine and its acid additionsalts with pharmaceutically acceptable acids, as stated above, areuseful as appetite depressants. They are characterized by a highanorectic effect, which can be measured in terms of reduction of foodintake or of weight decrease, and by a comparative lack of CNS-stimulant activity.

The invention further provides methods for preparing the novel base,N-(a-methyl-2,4-dichlorophenethyl)hydroxylamine. These methods comprisereducing 1-(2,4-- dichlorophenyl)-2-nitropropene with lithium aluminumhydride at low temperatures in the range between about minus 40 C. andabout 0 C. Ordinarily it will be convenient to dissolve both the lithiumaluminum hydride and the nitropropene compound in an inert organicsolvent, such as ether or tetrahydrofuran or mixtures thereof. Thereduction reaction is preferably eifected at temperatures between aboutminus 40 C. and minus 30 C.

The invention further provides methods of preparing acid addition saltsof N-(a-methyl-ZA-dichlorophenethyl)- hydroxylamine. A convenient methodcomprises reacting the base with an equivalent quantity of the desiredacid; or preferably with a slight excess over the equivalent quantity.Advantageously, this reaction is effected in liquid phase, i.e. withboth reactants in solution in inert solvents.

The invention is further disclosed in the following examples, which areillustrative but not limitative thereof. Temperatures are stated indegrees Centigrade, corrected.

Example 1 A quantity, 23 g., of 1-(2,4-dichlorophenyl)-2-nitropropenewas dissolved in 300 ml. of ether and the solution was added to a wellstirred solution of 3.7 g. of lithium aluminum hydride in 200 ml. ofether, previously cooled to minus 40 by means of an acetone-solid carbondioxide mixture. Cooling was continued during the reaction to keep thetemperature from rising above minus 30. After all of the nitropropenecompound had been added, the cooling bath was removed, and the lithiumaluminum hydride complex and unreacted lithium aluminum hydride weredecomposed by addition of 50 m1. of wet ether and 10 ml. of saturatedaqueous sodium sulfate solution. The granular precipitate was filteredoff and was washed with ml. of ether. The ether filtrate was combinedwith the ether washings, and the combined solutions were extracted threetimes, each time with 100 ml. of 1 N hydrochloric acid. The aqueous acidextracts were combined, adjusted to pH 9 by addition of saturatedaqueous sodium carbonate solution, and then the mixture was extractedthree times, each time with 100 ml. of ether. The combined etherextracts were washed with water, dried with sodium sulfate, andevaporated to dryness. There was thus obtained a white solid, N (amethyl 2,4 dichlorophenethyl)-hydroxylamine, M.P. 79-80".

Example 2 Ten g. of the end product of Example 1 was dissolved in 50 ml.of ether and mixed with a solution of 10 g. of p-toluene-sulfonic acidin 200 m1. of ether. The precipitated solid material was filtered 055and recrystallized from acetonitrile. The compound,N-(u-methyI-ZA-dichlorophenethyl)hydroxylamine p-toluenesulfonate, thusobtained melted at 153.

An additional quantity of 10 g. of N-(a-1nethyl-2/dichlorophenethyl)hydroxylarnine, obtained as described in Example 1,was dissolved in 50 ml. of ether and Was reacted with a solution of 5 g.of oxalic acid in 50 ml. of ether. The solid material obtained wasrecrystallized from ethanol/ ether. There was thus obtained the neutraloxalate of N-(a-methyl-Z,4-dichlorophenethyl)hydroxylamine, MP. 149l50.

An additional quantity of 5 g. of N-(wmethyl-ZA-dichlorophenethyl)hydroxylaminc, obtained as described in Example 1, wasdissolved in 25 ml. of ether and the solution was reacted with 10 ml. of10% (w./v.) ethereal hydrochloric acid. The solvent was evaporated invacuo, leaving N (a methyl-2,4-dichlorophenethyl)hydroxylaminehydrochloride as an oil which did not crystallize readily.

An additional quantity of 5 g. ofN-(a-methyl-2,4-dichlorophenethyl)hydroxylamine, obtained as describedin Example 1, was dissolved in 20 ml. of ethanol and the solution wasreacted with 8 ml. of 20% (w./v.) aqueous nitric acid. The solvent wasevaporated in vacuo. The N (a-methyl-2,4-dichlorophenethyl)hydroxylamine nitrate remained as an oil,which did not crystallize readily.

An additional quantity, 5 g., of the base, obtained as described inExample 1, was dissolved in 30 ml. of ethanol and the solution wasreacted with 6 ml. of 20% (w./v.) aqueous sulfuric acid. Afterevaporation of the solvents, the N (o;methyl-2,4dichlorophenethyl)hydroxylamine sulfate was obtained as anoil, which did not crystallize readily.

An additional quantity, 5 g., of the base, obtained as described inExample 1, was dissolved in 25 ml. of ether and the solution was reactedwith 3 ml. of 50% (w./v.) methanolic phosphoric acid. The solvents wereevaporated in vacuo, leaving an oil, N-(u-rnethyl-2,4-dichlorophenethyl) hydroxylamine phosphate.

2,233,823 Susic et a1. Mar. 4, 1941 4 2,495,404 Biedel'mann Jan. 24,1950 2,527,810 Goldberg et a1. Oct. 31, 1950 2,709,700 Szabo et a1. May31, 1955 2,852,562 Surrey Sept. 16, 1958 FOREIGN PATENTS 790,167 GreatBritain Feb. 5, 1958 OTHER REFERENCES Schales: J. Am. Chem. Soc., '01.74, 1952, page 4488.

Marsh: 3 our. Pharm. and Exp. Therap., v01. 94, page 195.

Gilsdorf et 21.: Jour. Am. Chem. Soc., vol. 74, pages 1837 to 1842(1952).

Compass Rendus, vol. 198, page 1867 (1934).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF N - (A -METHYL-2,4-DICHLOROPHENETHYL)HYDROXYLAMINE AND ACID ADDITION SALTSTHEREOF WITH PHARMACEUTICALLY ACCEPTABLE ACIDS.